IL302775A

IL302775A - Aromatic boron-containing compounds and insulin analogs

Aromatic boron-containing compounds and insulin analogs

Info

Publication number: IL302775A
Authority: IL; Israel
Prior art keywords: borono; pct; dihydrobenzo; hydroxy; oxaborole
Prior art date: 2020-11-19

Application number

IL302775A

Other languages

English (en)

Hebrew (he)

Original Assignee

Protomer Tech Inc

Priority date

2020-11-19

Filing date

2021-11-18

Publication date

2023-07-01

2021-11-18 Application filed by Protomer Tech Inc filed Critical Protomer Tech Inc

2023-07-01 Publication of IL302775A publication Critical patent/IL302775A/en

Links

NOESYZHRGYRDHS-UHFFFAOYSA-N insulin Chemical class N1C(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(NC(=O)CN)C(C)CC)CSSCC(C(NC(CO)C(=O)NC(CC(C)C)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CCC(N)=O)C(=O)NC(CC(C)C)C(=O)NC(CCC(O)=O)C(=O)NC(CC(N)=O)C(=O)NC(CC=2C=CC(O)=CC=2)C(=O)NC(CSSCC(NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2C=CC(O)=CC=2)NC(=O)C(CC(C)C)NC(=O)C(C)NC(=O)C(CCC(O)=O)NC(=O)C(C(C)C)NC(=O)C(CC(C)C)NC(=O)C(CC=2NC=NC=2)NC(=O)C(CO)NC(=O)CNC2=O)C(=O)NCC(=O)NC(CCC(O)=O)C(=O)NC(CCCNC(N)=N)C(=O)NCC(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC=CC=3)C(=O)NC(CC=3C=CC(O)=CC=3)C(=O)NC(C(C)O)C(=O)N3C(CCC3)C(=O)NC(CCCCN)C(=O)NC(C)C(O)=O)C(=O)NC(CC(N)=O)C(O)=O)=O)NC(=O)C(C(C)CC)NC(=O)C(CO)NC(=O)C(C(C)O)NC(=O)C1CSSCC2NC(=O)C(CC(C)C)NC(=O)C(NC(=O)C(CCC(N)=O)NC(=O)C(CC(N)=O)NC(=O)C(NC(=O)C(N)CC=1C=CC=CC=1)C(C)C)CC1=CN=CN1 NOESYZHRGYRDHS-UHFFFAOYSA-N 0.000 title claims description 438
150000001875 compounds Chemical class 0.000 title claims description 319
125000003118 aryl group Chemical group 0.000 title claims description 173
ZOXJGFHDIHLPTG-UHFFFAOYSA-N Boron Chemical compound [B] ZOXJGFHDIHLPTG-UHFFFAOYSA-N 0.000 title claims description 120
229910052796 boron Inorganic materials 0.000 title claims description 112
DHMQDGOQFOQNFH-UHFFFAOYSA-N Glycine Chemical compound NCC(O)=O DHMQDGOQFOQNFH-UHFFFAOYSA-N 0.000 claims description 303
102000004877 Insulin Human genes 0.000 claims description 232
108090001061 Insulin Proteins 0.000 claims description 232
229940125396 insulin Drugs 0.000 claims description 203
150000001412 amines Chemical class 0.000 claims description 186
-1 (2S,4S)-4-(3-borono-5-nitrobenzamido)-l-(3-borono-5-nitrobenzoyl)pyrrolidine-2- carbonyl Chemical group 0.000 claims description 183
239000004471 Glycine Substances 0.000 claims description 149
239000008186 active pharmaceutical agent Substances 0.000 claims description 129
125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 102
108090000765 processed proteins & peptides Proteins 0.000 claims description 99
125000000217 alkyl group Chemical group 0.000 claims description 91
125000003277 amino group Chemical group 0.000 claims description 86
235000001014 amino acid Nutrition 0.000 claims description 84
150000001413 amino acids Chemical class 0.000 claims description 81
102000004196 processed proteins & peptides Human genes 0.000 claims description 75
229920001184 polypeptide Polymers 0.000 claims description 72
ZADPBFCGQRWHPN-UHFFFAOYSA-N boronic acid Chemical compound OBO ZADPBFCGQRWHPN-UHFFFAOYSA-N 0.000 claims description 66
229940088679 drug related substance Drugs 0.000 claims description 62
238000000034 method Methods 0.000 claims description 57
PBGKTOXHQIOBKM-FHFVDXKLSA-N insulin (human) Chemical compound C([C@@H](C(=O)N[C@@H](CC(C)C)C(=O)N[C@H]1CSSC[C@H]2C(=O)N[C@H](C(=O)N[C@@H](CO)C(=O)N[C@H](C(=O)N[C@H](C(N[C@@H](CO)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H](CC=3C=CC(O)=CC=3)C(=O)N[C@@H](CSSC[C@H](NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3C=CC(O)=CC=3)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=3NC=NC=3)NC(=O)[C@H](CO)NC(=O)CNC1=O)C(=O)NCC(=O)N[C@@H](CCC(O)=O)C(=O)N[C@@H](CCCNC(N)=N)C(=O)NCC(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC=CC=1)C(=O)N[C@@H](CC=1C=CC(O)=CC=1)C(=O)N[C@@H]([C@@H](C)O)C(=O)N1[C@@H](CCC1)C(=O)N[C@@H](CCCCN)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(=O)N[C@@H](CC(N)=O)C(O)=O)=O)CSSC[C@@H](C(N2)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C(C)C)NC(=O)[C@@H](NC(=O)CN)[C@@H](C)CC)[C@@H](C)CC)[C@@H](C)O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CC(N)=O)NC(=O)[C@@H](NC(=O)[C@@H](N)CC=1C=CC=CC=1)C(C)C)C1=CN=CN1 PBGKTOXHQIOBKM-FHFVDXKLSA-N 0.000 claims description 49
239000000203 mixture Substances 0.000 claims description 48
125000005647 linker group Chemical group 0.000 claims description 46
235000018977 lysine Nutrition 0.000 claims description 45
150000002009 diols Chemical class 0.000 claims description 43
125000002887 hydroxy group Chemical group [H]O* 0.000 claims description 42
239000000813 peptide hormone Substances 0.000 claims description 40
125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 claims description 40
KDXKERNSBIXSRK-UHFFFAOYSA-N Lysine Natural products NCCCCC(N)C(O)=O KDXKERNSBIXSRK-UHFFFAOYSA-N 0.000 claims description 38
KDXKERNSBIXSRK-YFKPBYRVSA-N L-lysine Chemical compound NCCCC[C@H](N)C(O)=O KDXKERNSBIXSRK-YFKPBYRVSA-N 0.000 claims description 36
239000004472 Lysine Substances 0.000 claims description 36
210000004369 blood Anatomy 0.000 claims description 33
239000008280 blood Substances 0.000 claims description 33
229910052757 nitrogen Inorganic materials 0.000 claims description 33
ONIBWKKTOPOVIA-UHFFFAOYSA-N Proline Chemical compound OC(=O)C1CCCN1 ONIBWKKTOPOVIA-UHFFFAOYSA-N 0.000 claims description 32
125000004042 4-aminobutyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])C([H])([H])N([H])[H] 0.000 claims description 30
125000003588 lysine group Chemical class [H]N([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])(N([H])[H])C(*)=O 0.000 claims description 30
239000002253 acid Substances 0.000 claims description 29
125000001072 heteroaryl group Chemical group 0.000 claims description 29
229910052740 iodine Inorganic materials 0.000 claims description 29
101000976075 Homo sapiens Insulin Proteins 0.000 claims description 28
229910052739 hydrogen Inorganic materials 0.000 claims description 28
230000021615 conjugation Effects 0.000 claims description 27
206010012601 diabetes mellitus Diseases 0.000 claims description 27
125000000524 functional group Chemical group 0.000 claims description 27
235000000346 sugar Nutrition 0.000 claims description 27
102000015731 Peptide Hormones Human genes 0.000 claims description 26
108010038988 Peptide Hormones Proteins 0.000 claims description 26
150000001408 amides Chemical class 0.000 claims description 26
102000004169 proteins and genes Human genes 0.000 claims description 26
108090000623 proteins and genes Proteins 0.000 claims description 26
125000000753 cycloalkyl group Chemical group 0.000 claims description 25
JNCMHMUGTWEVOZ-UHFFFAOYSA-N F[CH]F Chemical compound F[CH]F JNCMHMUGTWEVOZ-UHFFFAOYSA-N 0.000 claims description 24
108010081348 HRT1 protein Hairy Proteins 0.000 claims description 24
102100021881 Hairy/enhancer-of-split related with YRPW motif protein 1 Human genes 0.000 claims description 24
150000004820 halides Chemical class 0.000 claims description 24
125000000539 amino acid group Chemical group 0.000 claims description 23
229910052731 fluorine Inorganic materials 0.000 claims description 23
229910052736 halogen Inorganic materials 0.000 claims description 23
150000002367 halogens Chemical class 0.000 claims description 23
125000000956 methoxy group Chemical group [H]C([H])([H])O* 0.000 claims description 23
235000018102 proteins Nutrition 0.000 claims description 23
FERIUCNNQQJTOY-UHFFFAOYSA-N Butyric acid Chemical compound CCCC(O)=O FERIUCNNQQJTOY-UHFFFAOYSA-N 0.000 claims description 22
229910052698 phosphorus Inorganic materials 0.000 claims description 22
229910052700 potassium Inorganic materials 0.000 claims description 21
229910052794 bromium Inorganic materials 0.000 claims description 20
229910052801 chlorine Inorganic materials 0.000 claims description 20
125000001188 haloalkyl group Chemical group 0.000 claims description 20
125000000113 cyclohexyl group Chemical group [H]C1([H])C([H])([H])C([H])([H])C([H])(*)C([H])([H])C1([H])[H] 0.000 claims description 19
239000003814 drug Substances 0.000 claims description 19
229910052760 oxygen Inorganic materials 0.000 claims description 18
125000003396 thiol group Chemical group [H]S* 0.000 claims description 18
229910052721 tungsten Inorganic materials 0.000 claims description 18
229910052727 yttrium Inorganic materials 0.000 claims description 18
150000001299 aldehydes Chemical class 0.000 claims description 17
125000003178 carboxy group Chemical group [H]OC(*)=O 0.000 claims description 17
125000002924 primary amino group Chemical group [H]N([H])* 0.000 claims description 17
150000003839 salts Chemical class 0.000 claims description 17
125000000876 trifluoromethoxy group Chemical group FC(F)(F)O* 0.000 claims description 17
150000008574 D-amino acids Chemical class 0.000 claims description 16
JCXJVPUVTGWSNB-UHFFFAOYSA-N Nitrogen dioxide Chemical compound O=[N]=O JCXJVPUVTGWSNB-UHFFFAOYSA-N 0.000 claims description 16
125000001889 triflyl group Chemical group FC(F)(F)S(*)(=O)=O 0.000 claims description 16
125000001500 prolyl group Chemical group [H]N1C([H])(C(=O)[*])C([H])([H])C([H])([H])C1([H])[H] 0.000 claims description 15
229910052720 vanadium Inorganic materials 0.000 claims description 15
125000002252 acyl group Chemical group 0.000 claims description 14
125000001434 methanylylidene group Chemical group [H]C#[*] 0.000 claims description 14
229940079593 drug Drugs 0.000 claims description 13
230000001225 therapeutic effect Effects 0.000 claims description 13
150000001350 alkyl halides Chemical class 0.000 claims description 12
229910052717 sulfur Inorganic materials 0.000 claims description 12
XUJNEKJLAYXESH-UHFFFAOYSA-N cysteine Natural products SCC(N)C(O)=O XUJNEKJLAYXESH-UHFFFAOYSA-N 0.000 claims description 11
235000018417 cysteine Nutrition 0.000 claims description 11
102000051325 Glucagon Human genes 0.000 claims description 10
108060003199 Glucagon Proteins 0.000 claims description 10
MASNOZXLGMXCHN-ZLPAWPGGSA-N glucagon Chemical compound C([C@@H](C(=O)N[C@H](C(=O)N[C@@H](CCC(N)=O)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](CCSC)C(=O)N[C@@H](CC(N)=O)C(=O)N[C@@H]([C@@H](C)O)C(O)=O)C(C)C)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](C)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CCCNC(N)=N)NC(=O)[C@H](CO)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CCCCN)NC(=O)[C@H](CO)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(N)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](N)CC=1NC=NC=1)[C@@H](C)O)[C@@H](C)O)C1=CC=CC=C1 MASNOZXLGMXCHN-ZLPAWPGGSA-N 0.000 claims description 10
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HNDVDQJCIGZPNO-UHFFFAOYSA-N histidine Natural products OC(=O)C(N)CC1=CN=CN1 HNDVDQJCIGZPNO-UHFFFAOYSA-N 0.000 claims description 10
238000004519 manufacturing process Methods 0.000 claims description 10
201000009104 prediabetes syndrome Diseases 0.000 claims description 10
HXITXNWTGFUOAU-UHFFFAOYSA-N phenylboronic acid Chemical compound OB(O)C1=CC=CC=C1 HXITXNWTGFUOAU-UHFFFAOYSA-N 0.000 claims description 9
150000003384 small molecules Chemical class 0.000 claims description 9
150000008163 sugars Chemical class 0.000 claims description 9
108010088751 Albumins Proteins 0.000 claims description 8
102000009027 Albumins Human genes 0.000 claims description 8
WHUUTDBJXJRKMK-UHFFFAOYSA-N Glutamic acid Natural products OC(=O)C(N)CCC(O)=O WHUUTDBJXJRKMK-UHFFFAOYSA-N 0.000 claims description 8
ONIBWKKTOPOVIA-BYPYZUCNSA-N L-Proline Chemical compound OC(=O)[C@@H]1CCCN1 ONIBWKKTOPOVIA-BYPYZUCNSA-N 0.000 claims description 8
235000013922 glutamic acid Nutrition 0.000 claims description 8
235000013930 proline Nutrition 0.000 claims description 8
150000003335 secondary amines Chemical class 0.000 claims description 8
208000001145 Metabolic Syndrome Diseases 0.000 claims description 7
238000009472 formulation Methods 0.000 claims description 7
108010004460 Gastric Inhibitory Polypeptide Proteins 0.000 claims description 6
102100039994 Gastric inhibitory polypeptide Human genes 0.000 claims description 6
208000002705 Glucose Intolerance Diseases 0.000 claims description 6
OUYCCCASQSFEME-QMMMGPOBSA-N L-tyrosine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-QMMMGPOBSA-N 0.000 claims description 6
HCHKCACWOHOZIP-UHFFFAOYSA-N Zinc Chemical compound [Zn] HCHKCACWOHOZIP-UHFFFAOYSA-N 0.000 claims description 6
UCMIRNVEIXFBKS-UHFFFAOYSA-N beta-alanine Chemical compound NCCC(O)=O UCMIRNVEIXFBKS-UHFFFAOYSA-N 0.000 claims description 6
150000001732 carboxylic acid derivatives Chemical class 0.000 claims description 6
125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 6
125000000291 glutamic acid group Chemical group N[C@@H](CCC(O)=O)C(=O)* 0.000 claims description 6
125000000487 histidyl group Chemical group [H]N([H])C(C(=O)O*)C([H])([H])C1=C([H])N([H])C([H])=N1 0.000 claims description 6
201000001421 hyperglycemia Diseases 0.000 claims description 6
YIYBQIKDCADOSF-UHFFFAOYSA-N pent-2-enoic acid Chemical compound CCC=CC(O)=O YIYBQIKDCADOSF-UHFFFAOYSA-N 0.000 claims description 6
230000000069 prophylactic effect Effects 0.000 claims description 6
125000000999 tert-butyl group Chemical group [H]C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 claims description 6
OUYCCCASQSFEME-UHFFFAOYSA-N tyrosine Natural products OC(=O)C(N)CC1=CC=C(O)C=C1 OUYCCCASQSFEME-UHFFFAOYSA-N 0.000 claims description 6
NQPDZGIKBAWPEJ-UHFFFAOYSA-N valeric acid Chemical compound CCCCC(O)=O NQPDZGIKBAWPEJ-UHFFFAOYSA-N 0.000 claims description 6
229910052725 zinc Inorganic materials 0.000 claims description 6
239000011701 zinc Substances 0.000 claims description 6
HJARPUISZGVEPE-UHFFFAOYSA-N B(O)(O)C=1C=C(C(=O)NCCCN(CC(=O)O)C(C2=CC(=CC(=C2)[N+](=O)[O-])B(O)O)=O)C=C(C=1)[N+](=O)[O-] Chemical compound B(O)(O)C=1C=C(C(=O)NCCCN(CC(=O)O)C(C2=CC(=CC(=C2)[N+](=O)[O-])B(O)O)=O)C=C(C=1)[N+](=O)[O-] HJARPUISZGVEPE-UHFFFAOYSA-N 0.000 claims description 5
DTHNMHAUYICORS-KTKZVXAJSA-N Glucagon-like peptide 1 Chemical compound C([C@@H](C(=O)N[C@@H]([C@@H](C)CC)C(=O)N[C@@H](C)C(=O)N[C@@H](CC=1C2=CC=CC=C2NC=1)C(=O)N[C@@H](CC(C)C)C(=O)N[C@@H](C(C)C)C(=O)N[C@@H](CCCCN)C(=O)NCC(=O)N[C@@H](CCCNC(N)=N)C(N)=O)NC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CCCCN)NC(=O)[C@H](C)NC(=O)[C@H](C)NC(=O)[C@H](CCC(N)=O)NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](CC(C)C)NC(=O)[C@H](CC=1C=CC(O)=CC=1)NC(=O)[C@H](CO)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC(O)=O)NC(=O)[C@H](CO)NC(=O)[C@@H](NC(=O)[C@H](CC=1C=CC=CC=1)NC(=O)[C@@H](NC(=O)CNC(=O)[C@H](CCC(O)=O)NC(=O)[C@H](C)NC(=O)[C@@H](N)CC=1N=CNC=1)[C@@H](C)O)[C@@H](C)O)C(C)C)C1=CC=CC=C1 DTHNMHAUYICORS-KTKZVXAJSA-N 0.000 claims description 5
239000000872 buffer Substances 0.000 claims description 5
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125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 5
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210000000496 pancreas Anatomy 0.000 claims description 5
125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 claims description 5
125000006552 (C3-C8) cycloalkyl group Chemical group 0.000 claims description 4
101710198884 GATA-type zinc finger protein 1 Proteins 0.000 claims description 4
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125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims description 4
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XBDQKXXYIPTUBI-UHFFFAOYSA-N dimethylselenoniopropionate Natural products CCC(O)=O XBDQKXXYIPTUBI-UHFFFAOYSA-N 0.000 claims description 4
DUWWHGPELOTTOE-UHFFFAOYSA-N n-(5-chloro-2,4-dimethoxyphenyl)-3-oxobutanamide Chemical compound COC1=CC(OC)=C(NC(=O)CC(C)=O)C=C1Cl DUWWHGPELOTTOE-UHFFFAOYSA-N 0.000 claims description 4
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KRKNYBCHXYNGOX-UHFFFAOYSA-K Citrate Chemical compound [O-]C(=O)CC(O)(CC([O-])=O)C([O-])=O KRKNYBCHXYNGOX-UHFFFAOYSA-K 0.000 claims description 3
101000623061 Drosophila melanogaster 40S ribosomal protein S26 Proteins 0.000 claims description 3
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KJSIWDSWXIJKNO-SFHVURJKSA-N N[C@@H](CCCCN(CC1=CC(B(O)O)=CC=C1)C(C1=CC([N+]([O-])=O)=CC(B(O)O)=C1)=O)C(N)=O Chemical compound N[C@@H](CCCCN(CC1=CC(B(O)O)=CC=C1)C(C1=CC([N+]([O-])=O)=CC(B(O)O)=C1)=O)C(N)=O KJSIWDSWXIJKNO-SFHVURJKSA-N 0.000 claims description 3
150000001298 alcohols Chemical class 0.000 claims description 3
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